Molecular Breast Imaging

Transcription

1 Molecular Breast Imaging Development of a Low-Dose Screening Test for Dense Breasts Conflict of Interest Royalties for technologies licensed to Gamma Medica Ideas Carrie B. Hruska, Ph.D. Department of Radiology Division of Medical Physics Mayo Clinic, Rochester, MN Michael O Connor, PhD Deborah Rhodes, MD Mayo s MBI Team Judy Boughey, MD Carrie Hruska, PhD Nicole Sandhu, MD, PhD Amy Conners, MD Bobby Maxwell, MD Dietlind Wahner- Roedler, MD Cindy Tortorelli, MD Overview Current methods for screening in dense breasts Nuclear Medicine s role in breast imaging Low-Dose Molecular Breast Imaging (MBI) Screening in dense breasts Other applications Limitations and advantages Future developments Beth Connelly Tammy Hudson Roxanne Pederson Karlie Gottwald, CNMT Carley Pletta, CNMT

2 Breast Cancer Screening Guidelines November 2009 In US, women are urged to get annual screening mammograms starting at age 40 - Long debate about use in women ages USPSTF has recommended against use of routine mammography in women under 50 twice since Breast exam guidelines now call for less testing Change debated Potential harm of frequent mammograms outweighs benefit, task force says By Rob Stein, Washington Post Staff Writer Tuesday, November 17, 2009 "Tens of thousands of lives are being saved by mammography screening, and these idiots want to do away with it," said Daniel B. Kopans, a radiology professor at Harvard Medical School. "It's crazy -- unethical, really."

3 Support of continued annual screening starting at age 40 American Cancer Society American College of Radiology American College of Obstetrics and Gynecology Susan G Komen for the Cure Radiologic Society of North America Medical Centers Breast Cancer Screening Guidelines Should women be screened? yes, mortality benefit has been shown 17 days later, Congress banned the use of these new guidelines in determining insurance coverage Only mammography has demonstrated mortality benefit As much as two-thirds of the decline in breast cancer mortality can be attributed to screening mammography Cancer Intervention and Surveillance Network, NEJM 2005;353: Breast Cancer Screening Guidelines Should women be screened? yes, mortality benefit has been shown When to start? How often? Why is benefit of mammography less in younger women?

4 Why is benefit less for younger women? Breast Density Most important factor in failure of mammography to detect cancer Explains 68% of decreased sensitivity in younger women Breast Density Classification Fatty Replaced Scattered densities Heterogeneously dense Extremely dense Buist et al: JNCI, < 25% dense 25-50% dense 51-75% dense >75% dense Breast Density by Age Fatty Performance of mammography in dense breasts Females with dense breasts (%) Dense Report sensitivity of mammography in extremely dense breasts ranges from 30-63% Using follow-up mammogram findings as reference standard probably results in overestimate of true sensitivity Age (yr) 80% have dense breasts at age 40 40% have dense breasts at age 80 Kopans: Breast Imaging, 2 nd ed, Mandelson MT et al. JNCI 2000;92: Carney PA et al, Ann Intern Med 2003;138: Pisano et al, Radiology 2008;246:

5 Digital Mammography ACRIN DMIST trial 50,000 women screening with both film and digital mammography Single subgroup in whom digital was significantly better than film: pre- or peri-menopausal women <50 years with dense breasts Sensitivity: 59% digital, 27% film Density is an independent risk factor Density strongly associated with risk of developing breast cancer (4-6 x that of fatty replaced breasts) Greater likelihood of cancer recurrence in dense breasts Pisano et al. NEJM 2005; 353:17 Pisano et al, Radiology 2008;246: Boyd NF et al. Cancer Epidemiol Biomarkers Prev. 1998; 7: Habel LA et al. Cancer Epidemiol Biomarkers Prev 2010; 19: Risk factor Breast Density Comparative Relative Risks Relative risk BRCA mutation 20 Lobular carcinoma in situ 8-10 Dense breast parenchyma 4-6 Personal history of breast cancer 3-4 Family history (1 relative) 2.1 Postmenopausal obesity 1.5 Prempro (WHI) 1.26 Population Attributable Risk Breast density: 33% Family history: 9% BRCA 1, 2 mutations: 5% Boyd NF et al. JNCI 1995; 87: Cuzick J. The Breast 2003; 12:

6 What are the current screening alternatives for women with dense breasts? Tomosynthesis Ultrasound MRI Tomosynthesis (See previous lecture for expert review) Recently FDA-approved Multiple studies ongoing ACRIN is likely to fund clinical trial Ultrasound ACRIN 6666 trial (high risk and dense breasts) physician-performed WBU Increased diagnostic yield from 7.6/1,000 with mammography alone to 11.8/1,000 by adding WBU Substantial number of false positives, PPV = 9% Berg et al, JAMA Automated Whole Breast Ultrasound Increased diagnostic yield from 3.6/1,000 with mammography alone to 7.2/1,000 by adding AWBU PPV = 38% Many images to review Kelly et al, Eur Radiol 2010; 20:

7 Magnetic Resonance Imaging In hands of expert readers: Very high sensitivity (approaching 100%) Acceptable specificity ACS issued 2007 recommendations Annual screening MRI in women with risk >20% Not enough evidence to recommend for screening in dense breasts ACS recognized that specificity in community practice setting can be ~50% Nuclear Medicine Imaging of the Breast Scintimammography / Breast Scintigraphy Breast-Specific Gamma Imaging (BSGI) Positron Emission Mammography (PEM) Molecular Breast Imaging (MBI) CA Cancer J Clin 2007;57: Scintimammography Refers to conventional scintillating gamma camera technology of 1990 s Bulky camera cannot be positioned close to the breast Interference from adjacent tissues (heart, liver) Poor sensitivity for lesions < 1 cm Scintimammogram (lateral view) Patient in prone position Scintimammography Effect of Breast Thickness on Lesion Detection 6-8 cm 2-3 cm Tumor Depth = 7 cm Tumor Depth = 3 cm Courtesy of MK O Connor, unpublished image

8 Dedicated Nuclear Medicine Detectors Dedicated Nuclear Medicine Detectors Allow positioning in standard mammographic views Minimal interference from adjacent tissues Better spatial resolution due to: Close contact of breast with detector Pixilated detectors BSGI Dilon Diagnostics Single Photon Detection Multicrystal Sodium Iodide (NaI) + PMTs PEM Naviscan Coincidence Detection Scanning arrays of LYSO crystals Semiconductor Detector Cadmium Zinc Telluride Scintillating vs. Semiconductor Detectors Scintillator (NaI) Converts gamma ray photons to light Photomultiplier tubes (PMT) converts light to electrons Semiconductor (CZT) Direct conversion: gamma rays to electrons Improved energy and spatial resolution over NaI g-ray Collimator 4 cm x 4 cm cadmium zinc telluride (CZT) module Pixel size: 1.6 mm or 2.5 mm Positioning and Summing Circuits NaI crystal Light Guide PMTs

9 Our first prototype: Molecular Breast Imaging CZT gamma camera Molecular Breast Imaging Systems FDA-approved, clinically available Dual-head CZT detectors Gamma Medica LumaGem GE Healthcare Discovery NM MBI Procedure Tc-99m sestamibi injected IV Patient positioned by specially trained technologist Imaging begins immediately after injection Two views of each breast acquired (CC and MLO) Light, pain-free compression Tc-99m sestamibi Developed for cardiac imaging FDA-approved for diagnostic breast imaging in 1997 Exact mechanism of uptake in cancer uncertain Proportional to blood flow and mitotic activity Imaging can commence minutes after injection Effective half-life = 3 hours Uptake not influenced by breast density

10 Could MBI Find Small Breast Tumors? 18 mm 10 mm 3 mm Two Heads are Better than One 2 Mammogram 20 mm MBI 20 mm Additional 10 mm tumor 3 tumors 17, 6, 3 mm Tumor extending to nipple Extensive tumor Missed cancers occurred more often in women with large compressed breast thickness Could MBI Find Small Breast Tumors? Detection of cancer in 88 patients with 128 tumors Better detection with Dual-head MBI, example 1 Infiltrating ductal carcinoma, 1.5 x 1.3 x 1.2 cm Tumor Size # of tumors Single head MBI Dual head MBI P-value 10 mm 61 68% 82% All 88 80% 90% < Hruska et al, AJR 2008; 191: Images courtesy of Dr. Judy Boughey, Mayo Clinic

11 Better detection with Dual-head MBI, example cm invasive lobular carcinoma MBI for Screening in Dense Breasts Funded by Komen for the Cure Eligible women: Asymptomatic Presenting for routine screening mammography Heterogeneously or extremely dense breasts based on past prior mammogram Images courtesy of Dr. Judy Boughey, Mayo Clinic Rhodes et al. Radiology, Jan Results 1007 patients enrolled, 936 with known cancer status Mean age of patients: cancers diagnosed 1 by mammography only 8 by MBI only 2 by both 1 by neither (detected at next annual mammogram) Examples of Mammographically Occult Cancers Detected on MBI 4 mm IDC + 19 mm DCIS 10 mm tubulolobular 12 mm DCIS 51 mm ILC Rhodes et al. Radiology

12 Cumulative Cancer Mortality Proof of Concept: MBI in Screening Setting Diagnostic yield increased detection from 3.2/1,000 for mammography alone to 10.7/1,000 by adding MBI (p=0.016) Sensitivity: 3/11 for mammography, 9/11 for MBI Specificity: 91% for mammography, 93% for MBI PPV of MBI = 12%, four times higher than mammography (3%) (P=0.01) Proof of concept: Need to verify findings using low dose (4 mci) MBI Radiation Risks of MBI Modality Mammography (2-view bilateral screen ) PEM (10 mci F-18 FDG) BSGI/ MBI (20-30 mci Tc-99m sestamibi) Dose to Breast (mgy) 3.7 (digital) 4.7 (film) Effective Dose (msv) 0.44 (digital) 0.56 (film) Single exam, age 40: LAR of Fatal Cancer Annual exams, ages 40-80: LAR of Fatal Cancer Effective Dose accounts for organ-specific doses and weighting factors, and represents the dose to the entire body; LAR = Lifetime Attributable Risk per 100,000 women Comparison with Background Radiation LAR of Fatal Cancer due to Annual Background Radiation per 100,000 women (birth to 80 years) U.S. Average (3.1 msv/year) ~1010 Colorado (~4.5 msv/year) Florida (~2.5 msv/year) ~1460 ~ mci MBI screening, age (~7.6 msv/year) ~ 450 Low-dose MBI screening, age (~1.2 msv/year) ~ Digital Mammography Tc-99m mibi (25 (4 mci) F-18 FDG (10 mci) Background Radiation Age (years) Data from: Hendrick RE, Radiology 2010; 257: , Data from: O Connor et al. Medical Physics 2010, 37 (12) O Connor et al. Medical Physics 2010, 37 (12)

13 MBI Dose Reduction Collimator Optimization For annual breast screening, target dose for MBI is 4 mci Tc-99m sestamibi 1.2 msv effective dose Equivalent to ~2 screening mammograms Intended screening interval would be 2 years MBI dose reduction schemes Optimization of collimator Use of widened energy window Post-acquisition image processing Hexagonal holes changed to square registered holes Improves active area, count sensitivity Holes closer together, switched from lead to tungsten Shorten bore, more count sensitive but give up resolution Dual-detector design means only ½ of breast needs adequate resolution for each detector Registered Tungsten Collimator CREATV MicroTech Potomac, MD O Connor et al. Medical Physics, vol 37 (12), December Weinmann et al. Medical Physics 2009; 36: Collimator Optimization MBI Dose Reduction: Wide Energy Acceptance Window MBI performed with conventional and optimized collimators ~3 gain in counts Dose 4 mci Tailing Effect in CZT: Good photopeak events mis-registered at lower energies Due to incomplete charge trapping in semiconductor MBI: detected multifocal invasive lobular carcinoma and nipple adenoma. Digital Mammography: benign stable findings O Connor et al. Proceedings of SPIE 2010; vol 7806 Standard collimator Optimized collimator Hruska et al. IEEE Trans Nuc Sci 2008; 55: O Connor et al. Proceedings of SPIE 2010; vol

14 MBI Dose Reduction: Wide Energy Acceptance Window MBI Dose Reduction: Wide Energy Acceptance Window MBI performed with conventional and widened energy window x gain in counts Tradeoff: more counts but some scatter at chest wall O Connor et al. Proceedings of SPIE 2010; vol 7806 O Connor et al. Proceedings of SPIE 2010; vol Low-Dose MBI: New Collimation and Wider Energy Window September mci Tc-99m sestamibi Low-dose screening Funded by Komen for the Cure Target recruitment: 2400 Accrual to date: mci dose Can simulate images at 2,4,and 6 mci doses 9 cancers diagnosed 8 detected by MBI 0 detected by mammography 1 found on prophylactic mastectomy PPV = 35% Same patient in December mci Tc-99m sestamibi Courtesy of Dr. Michael O Connor, Mayo Clinic

15 Mammogram 2010 Mammogram 2011 MBI 2011 Tubular Carcinoma 0.5 cm ILC 3.6 cm; LN+ DCIS 0.6 cm Read as extremely dense; Negative Read as extremely dense; Negative Final path Right Mastectomy: DCIS DCIS final path pending 1.9 cm IDC Patient unable to have MRI due to implanted device R CC R MLO Non-screening applications of MBI MBI in preoperative evaluation Mammogram: irregular nodule in UOQ at site of palpable abnormality Ultrasound: 2.3 cm irregular hypoechoic mass R CC R MLO index satellite Final Pathology: Infiltrating ductal carcinoma, grade III, forming 2 masses: 2.2 cm, and 0.9 cm MBI: Uptake in 2 foci, 2.5 cm and 0.9 cm MRI: index carcinoma -1.6 x 2.4 cm irregular enhancing mass; satellite lesion x 1.4 cm

16 Good correlation between MBI and MRI 9 mm cancer (Ductal Carcinoma In Situ) Neoadjuvant Therapy Case #1 Mammogram shows no change Pre-Therapy After 3 months of therapy Screen Mammogram MBI Breast MRI Neoadjuvant Therapy Case #1 MBI demonstrates pathologic complete response Neoadjuvant Therapy Case #2 MRI and MBI MRI Molecular Breast Imaging x 4.5 x 4.5 cm mass 2.0 x 1.1 x 2.0 cm mass Pre-therapy Post-therapy Pre-therapy Post-therapy Initial diagnosis: IDC with large Area of DCIS MRI: indicated residual disease Left Mastectomy: Surgical Pathology indicated no residual viable cancer

17 MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Fibroadenoma Biopsies with benign findings: ~3% of screening cases Benign Papilloma MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake

18 Follicular Phase Effect of Menstrual Cycle MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake Injection Luteal Phase MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake Injection Radiation MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake Injection Radiation Time to perform

19 MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake Injection Radiation Time to perform Biopsy capability in development MBI - Limitations and Disadvantages False positive findings in some cases of fibroadenomas, papillomas, fat necrosis. Uptake of Sestamibi is influenced by hormonal changes benign parenchymal uptake Injection Radiation Time to perform Biopsy capability in development Uncertain performance in DCIS Advantages of MBI Compared to mammography: Higher sensitivity in dense breasts Less compression; patient comfort Compared to MRI: Option if contraindication to MRI (claustrophobia, pacemaker, clips, impaired renal function) Generalizability Interpretation easy to learn Rapid interpretation Highly reproducible between readers, even those newly trained 5-fold less expensive than MRI, $600 vs $3000 at Mayo Future Developments in MBI Combined MBI / Ultrasound system with real-time MBI-guided biopsy in development Investigation of other radiopharmaceuticals Improved lesion detection / characterization Standardized reporting, terminology, and training course for MBI interpretation Collaboration with Dr. Wendie Berg (UPMC) Development of standardized QC tests and phantom for dedicated pixilated gamma cameras

20 Thank you! This work has been funded in part by the following: Mayo Foundation National Institute of Health Dept. of Defense Susan G Komen For the Cure Foundation Friends for an Earlier Breast Cancer Test